Background

Oligosaccharide modifications induce various functional changes in immune cells. We previously reported that the galactose-deficient fraction in fucosylated IgG oligosaccharides is increased with a decrease in beta-1,4-galactosyltransferase I (B4GalTI) in patients with Crohn's disease (CD) (Shinzaki S. et al. Am J Gastroenterol 2008). Recent reports demonstrate that B cells and immunoglobulins have protective roles in inflammatory bowel diseases (IBD). The roles of oligosaccharide alterations in CD, however, have not been investigated yet. In the present study we investigated a possible role of oligosaccharide modification in the pathophysiology of colitis using mice defective in glycosyltransferases.

Methods

Colitis severity was compared between B4galt1+/− and B4galt1+/+ mice. B cells isolated from B4galt1+/− and B4galt1+/+ mice were adoptively transferred to recombination activating gene (Rag) 2−/− mice, in which colitis was induced by CD4+CD62L+ T cells. Cell-surface glycan profiles were determined by lectin microarray. Cytokine production was determined in a co-culture of various types of cells isolated from either B4galt1+/− or B4galt1+/+ mice.

Results

Dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid-induced colitis was significantly ameliorated in B4galt1+/− mice, which have galactose deficiency in IgG oligosaccharides (similar to that of patients with CD) compared with B4galt1+/+ mice. Amelioration of colitis was associated with an increased interleukin-10 (IL-10) production from macrophages in B4galt1+/− mice. The amelioration of colitis in B4galt1+/− mice was lost in the absence of IL-10, indicating that IL-10 is indispensable for the protection of colitis in B4galt1+/− mice. Colitis in Rag2−/− mice transferred with CD4+CD62L+ T cells was ameliorated by co-transfer of B cells isolated from B4galt1+/−, but not from B4galt1+/+ mice. Lectin microarray and flow cytometric analysis revealed increased expression of polylactosamines on B4galt1+/− B cells and macrophages in comparison with B4galt1+/+ cells. The production of IL-10 from macrophages was induced via their direct interaction with B4galt1+/− B cells by cross-linking cell-surface polylactosamines by galectins. Moreover, alpha-1,6-fucosyltransferase (Fut8) deficient mice, which lack core fucose, also showed amelioration of DSS colitis.